The azetidinone of the below formula, which is the subject of the present invention, is a
therapeutically useful compound. It is disclosed in the product patent RE37721, which is a re-issue of U.S. Pat. No. 5,767,115. Different processes for its synthesis are also described therein.
This compound is a biologically active molecule and research has shown it to have the useful property of inhibiting the absorption of cholesterol from the intestine (J. Med. Chem. 1998, 41(6), 973). Since then this azetidinone—1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone—has been approved by the USFDA and other regulatory authorities worldwide for use in the lowering of cholesterol in humans. It is at present marketed under the names of Zetia™, Ezetrol™, Ezemibe™, Zient™ et cetera.
Many processes for the preparation of this cholesterol absorption inhibitor have been reported: most are total chemical synthesis and others have a few enzymatic steps. The product patent itself discusses various synthetic strategies. In general, the difference in the routes lies in the introduction of the 4-fluorophenyl group, which is at the end of the aliphatic side-chain, with respect to the formation of the azetidinone ring. The azetidinone ring is obtained by cyclization, which could be carried out after the three substituted-phenyl groups have been incorporated into the molecule. However, in an alternate method the same cyclization may be carried out first and then the 4-fluorophenyl group at the end of the side chain or, sometimes, the whole side chain is attached onto this ring. In the processes described in U.S. Pat. No. 6,207,822 and WO2007/119106 the 4-fluorophenyl moiety is part of the molecule which is then cyclized to form the 4-membered ring, whereas, U.S. Pat. No. 5,886,171 and U.S. Pat. No. 5,856,473 describe processes wherein the 4-fluorophenyl group is introduced later.
Of these two strategies, it has been observed that within the former approach also there are two different methods that revolve around the secondary hydroxyl group. In the synthesis of this 1,4-diphenylazetidinone, the hydroxyl group is always brought in by the reduction of the corresponding ketone. In certain processes the reduction of the ketone to form the alcohol is done in the first step itself, while in others the reduction to alcohol is preferred in the final stages. However, regardless of whether the reduction is carried out initially or later in the synthesis, the moiety therein has to be protected in order to avoid the formation of by-products that lead to lowering in the yield of the desired product. When reduction is done at the beginning then the resulting alcohol is protected by a suitable protecting group and if done later, then the pro-moiety, i.e. the ketone, is protected suitably.
The process that forms the present invention too follows the former strategy wherein the molecule comprising the three substituted phenyl groups is cyclized to create the azetidinone ring. Further, the ketone moiety on the side chain is protected until formation of the β-lactam ring and then deprotected and reduced stereospecifically to yield the desired product.